We have shown that invariant natural killer T (iNKT) cells mediate sepsis-induced end-organ changes and immune responses, including macrophage bacterial phagocytosis, a finding regulated by the check point protein program cell death receptor-1 (PD-1). Furthermore, PD-1 mediates mortality in both adult and neonatal murine sepsis as well as in surgical patients. Given our previous findings, we hypothesize that iNKT cells will also modulate neonatal sepsis survival, and that this effect is regulated in part through PD-1...

Introduction: Tumours connected with head and neck comprise about 5% of all tumours. The most frequent histological type of laryngeal carcinoma is squamous cell carcinoma. Different research projects suggest that the role of T lymphocytes might be significant in tumour development. iNKT cells are a new subpopulation of T cells and show cytotoxic activity against tumours. iNKT cells participate in modulating the function of other cells which have anti-tumour properties and secrete cytokines, which have pro-inflammatory and anti-inflammatory effects...

Invariant Natural killer T (iNKT) cells rapidly produce copious amounts of multiple cytokines after in vivo activation, allowing for the direct detection of a number of cytokines directly ex vivo. However, for some cytokines this approach is suboptimal. Here, we report technical variations that allow the improved detection of IL-4, IL-10, IL-13 and IL-17A ex vivo. Furthermore, we describe an alternative approach for stimulation of iNKT cells in vitro that allows a significantly improved detection of cytokines produced by iNKT cells...

Excessive interferon-α (IFN-α) production by innate immune cells is a hallmark of autoimmune diseases. What other cell type secretes IFN-α and how IFN-α affects immune cell metabolism and homeostasis in autoimmunity are largely unclear. Here, we report that autoimmune B cells, arising from two different B cell-specific genetic lesions in mice, secrete IFN-α. In addition, IFN-α, found in abundance in autoimmunity, elicited profound changes in the B cell lipidome, increasing their expression of glycosphingolipids (GSLs) and leading to their CD1d-mediated depletion of iNKT cells in vitro and in vivo...

Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti-PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy...

BACKGROUND: Based on the phenotypic and functional characteristics unconventional T-lymphocytes such as invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells link the innate and adaptive immune responses. Up to now data are scarce about their involvement in pulmonary disorders including chronic obstructive pulmonary disease (COPD). This study explores simultaneously the frequencies of iNKT and MAIT cells in the peripheral blood and sputum of stable and exacerbating COPD patients...

Invariant natural killer T (iNKT) cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co-inhibitory markers such as programmed death-1...

Major progress in cancer immunotherapies have been obtained by the use of tumor targeting strategies, in particular with the development of bi-functional fusion proteins such as ImmTacs or BiTes, which engage effector T cells for targeted elimination of tumor cells. Given the significance of invariant natural killer T (iNKT) cells in bridging innate and adaptive immunity, we have developed a bi-functional protein composed of the extracellular part of CD1d molecule that was genetically fused to an scFv fragment from high affinity antibodies against HER2 or CEA...

We and others have found that the functions of hepatic natural killer (NK) cells are inhibited but invariant NKT (iNKT) cells become activated after alcohol drinking, leaving a possibility that there exists interplay between NK cells and iNKT cells during alcoholic liver disease. Here, in a chronic plus single-binge ethanol consumption mouse model, we observed that NK cells and interferon-γ (IFN-γ) protected against ethanol-induced liver steatosis, as both wild-type (WT) mice treated with anti-asialo GM1 antibody and IFN-γ-deficient GKO mice developed more severe alcoholic fatty livers...

c-Maf belongs to the large Maf family of transcription factors and plays a key role in the regulation of cytokine production and differentiation of TH2, TH17, TFH, and Tr1 cells. Invariant natural killer T (iNKT) cells can rapidly produce large quantity of TH-related cytokines such as IFN-γ, IL-4, and IL-17A upon stimulation by glycolipid antigens, such as α-galactosylceramide (α-GalCer). However, the role of c-Maf in iNKT cells and iNKT cells-mediated diseases remains poorly understood. In this study, we demonstrate that α-GalCer-stimulated iNKT cells express c-Maf transcript and protein...

The role of sphingolipids (SLs) in the immune system has come under increasing scrutiny recently due to the emerging contributions that these important membrane components play in regulating a variety of immunological processes. The acyl chain length of SLs appears particularly critical in determining SL function. Here, we show a role for very-long acyl chain SLs (VLC-SLs) in invariant natural killer T (iNKT) cell maturation in the thymus and homeostasis in the liver. Ceramide synthase 2-null mice, which lack VLC-SLs, were susceptible to a hepatotropic strain of lymphocytic choriomeningitis virus, which is due to a reduction in the number of iNKT cells...

Short-term outcomes of solid organ transplantation have improved dramatically over the past several decades; however, long-term survival has remained static over the same time period, and chronic rejection remains a major cause of graft failure. The importance of donor, or 'passenger', lymphocytes to the induction of tolerance to allografts was recognized in the 1990s; however, their precise contribution to graft acceptance or rejection has not been elucidated. Recently, specialized populations of tissue-resident lymphocytes in nonlymphoid organs have been described...

Invariant natural killer T (iNKT) cells are a unique innate T lymphocyte population that possess cytolytic properties and profound immunoregulatory activities. iNKT cells play an important role in the immune surveillance of blood cancers. They predominantly recognize glycolipid antigens presented on CD1d, but their activation and cytolytic activities are not confined to CD1d expressing cells. iNKT cell stimulation and subsequent production of immunomodulatory cytokines serve to enhance the overall antitumor immune response...

BACKGROUND: CD1d-dependent invariant natural killer (iNKT) cells are found as either CD4 single positive (SP) or CD4/CD8 double negative (DN) cells in mice. The size of the CD8(+) iNKT population is extremely small. It is known that CD1d expression on developing thymocytes is sufficient for iNKT development and co-receptor choice, which is driven by Th-POK expression. This study aimed to examine the factors involved in the CD4/CD8 co-receptor choice of iNKT cells in addition to Th-POK-driven silencing of CD8 expression...

Long chain fatty acids (LCFAs) exert pro-inflammatory effects in vivo. However, little is known regarding the effect of LCFAs on invariant (i) NKT cell functions. Here, we report an inhibitory effect of saturated LCFAs on transcription factors in iNKT cells. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-γ production and reduced gata-3 and t-bet transcript levels in iNKT cells during TCR-mediated activation. In iNKT cells, PA was localized and induced dilation in the endoplasmic reticulum and increased the mRNA levels of downstream molecules of IRE1α RNase...

HBV eradication in Chronic Hepatitis B (CHB) subjects is rarely achieved with either nucleos(t)ide analogues (NA) or pegylated interferon (Peg-IFN), which both have a limited effect in restoring immune responses. 30 CHB subjects on long-term treatment with tenofovir (TDF) and HBV suppression were enrolled and randomized 1:2 to either receive Peg-IFN-α-2a add-on therapy or continue TDF alone. We studied γδT and iNKT frequency and function (by flow cytometry) at baseline, at 12 weeks and 12 weeks after the end of treatment...

This unit details methods for the isolation, in vitro expansion, and functional characterization of human iNKT cells. The term 'iNKT' derives from the fact that a large fraction of murine and some human NK marker+ T cells ('NKT') recognize the MHC class I-like CD1d protein and use an identical 'invariant' TCRα chain, which is generated in humans by precise Vα24 and Jα18 rearrangements with either no N-region diversity or subsequent trimming to identical or nearly identical amino acid sequence (hence, 'iNKT' cells)...

Common variable immunodeficiency (CVID) is a syndrome with predominantly defective B cell function. However, abnormalities in the number and function of other lymphocyte subpopulations in peripheral blood (PB) have been described in most patients. We have analysed the distribution of iNKT cell subpopulations in the PB of CVID patients and the ability of these cells to provide in vitro cognate B cell help. The total of iNKT cells was reduced in the PB of CVID patients, especially CD4+, CD4-/CD8- and CCR5+/CXCR3+...